Cryptococcus neoformans infections among HIV-infected individuals in the United States occurs at a prevalence rate of 5-10% and is a leading mycological cause of morbidity and mortality among AIDS patients. Studies have suggested that cell-mediated immunity (CMI) by T helper (Th) 1-type CD4+ T cells is the predominant host defense mechanism against C. neoformans infections. However, the detailed immunological response that would elicit protection against cryptococcal relapse or reinfection is yet to be defined. In our preliminary studies, we have shown that an experimental pulmonary infection with an interferon gamma (IFN-g)-producing C. neoformans strain in mice results in the induction of Th1-type CMI responses and resolution of the acute infection. Furthermore, we have for the first time demonstrated that prior challenge with an IFN-g-producing C. neoformans strain results in complete (100%) protection against a second pulmonary challenge with a pathogenic C. neoformans strain. Based on these results, we hypothesize that C. neoformans strains engineered to produce IFN-g can be used to determine the mechanism(s) involved in protective host immunity against pathogenic pulmonary C. neoformans infections. Therefore, we propose to use this model system to analyze protective anti-cryptococcal host immune responses using the following "Specific Aims": (1) To characterize the impact of local cryptococcal IFN-g production on the induction of host immunity against pulmonary cryptococcosis. (2) To determine the immune mechanism(s) that is responsible for resistance against re-infection with a pathogenic C. neoformans strain. (3) To evaluate the local pathology and cellular composition of the inflammatory response in mice resistant and susceptible to experimental pulmonary cryptococcosis. (4) To determine if the route of challenge with the IFN-g producing C. neoformans strain influences the development of protective immunity against pulmonary or disseminated C. neoformans infections. Cryptococcus neoformans is an opportunistic fungus that may cause life-threatening infections of the brain in individuals with suppressed immune systems. I am proposing to perform studies to define the parameters of which protective immune responses can be generated against C. neoformans infections. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections in immune compromised individuals.